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R A Baan

Publications and source records attributed to R A Baan.

At least 19 recordsLinked to original sources
PubMed2000

Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal development.

Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa resulting in embryotoxicity and developmental defects in their offspring. This study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa following treatment with the antineoplastic drug, cisplatin. The formation of spermatozoa cisplatin-DNA adducts showed dose and time-dependent increases both in vitro, and in vivo up to 168 h (7 days) after dosing. Treatment of rats with 10 mg cisplatin/kg resulted in spermatozoa Pt-GG adduct levels of approximately 1.0 fmol/microg DNA. When cisplatin-treated male rats were bred to untreated females 6-24 h after cisplatin administration, no adverse developmental effects or decreases in body weight were seen in the offspring although there was a trend towards increased early embryo mortality.

Animals↗
PubMed2000

Evaluation of the carcinogenic risks to humans associated with surgical implants and other foreign bodies - a report of an IARC Monographs Programme Meeting. International Agency for Research on Cancer.

A meeting was held within the International Agency for Research on Cancer (IARC) Programme on the Evaluation of Carcinogenic Risks to Humans of surgical implants and other foreign bodies. This meeting report summarises the types of materials considered, their wear and degradation, their cancer epidemiology in both humans and other animals, the published experimental carcinogenicity data and selected data on their toxic, including genotoxic, effects. Evaluations resulting in a classification of Group 2B (possibly carcinogenic to humans) were reached for: (1) polymeric implants prepared as thin smooth films [with the exception of poly(glycolic acid)]; (2) metallic implants prepared as thin smooth films; and (3) implanted foreign bodies consisting of metallic cobalt, metallic nickel and a particular alloy powder consisting of 66-67% nickel, 13-16% chromium and 7% iron. Group 3 classifications (not classifiable as to their carcinogenicity to humans) were made for: (1) organic polymeric materials as a group; (2) orthopaedic implants of complex composition and cardiac pacemakers; (3) silicone breast implants; (4) dental materials; and (5) ceramic implants.

Animals↗
PubMed1999

Induction of somatic mutations but not methylated DNA adducts in lambdalacZ transgenic mice by dichlorvos.

In order to examine the in vivo genotoxic activity of dichlorvos, lambdalacZ transgenic mice (Muta Mouse) were treated i.p. with single (4.4 or 11 mg/kg) or multiple (5 x 11 mg/kg) doses of this agent and sacrificed 4 h or 14 days post-treatment for DNA adduct measurement or mutant frequency analysis, respectively. Neither methylated DNA adducts nor an increase in mutant frequency were detected in the bone marrow, white blood cells, liver, spleen, lung, brain and sperm cells after the single doses. However, following multiple dosing a statistically significant 3-fold increase in mutant frequency was observed in the liver, while a non-statistically significant increase was observed in the bone marrow. In contrast, dimethylsulphate, a model methylating agent, gave rise to detectable DNA adducts but no increase in mutant frequency following i.p. administration of single (30 mg/kg) or multiple (10 x 6 mg/kg) doses.

Animals↗
PubMed1999

Methyl bromide causes DNA methylation in rats and mice but fails to induce somatic mutations in lambda lacZ transgenic mice.

Following single or multiple oral treatments of rats or lambda lacZ transgenic mice with methyl bromide, methylated DNA adducts (N7- and/or O6-methylguanine) were found at comparable levels in various tissues, including among others the glandular stomach, the forestomach and the liver. Multiple rat treatment resulted in substantial decreases in the repair enzyme O6-alkylguanine-DNA alkyltransferase which were probably due in part to direct interaction of the enzyme with methyl bromide. However, no induction of mutagenesis in the lacZ transgene could be detected in any tissue 14 days after single treatments of up to 50 mg/kg or after multiple treatments of as many as 10 daily treatments of 25 mg/kg MeBr.

Animals↗
PubMed1999

The potential of plantinum-DNA adduct determination in ex vivo treated tumor fragments for the prediction of sensitivity to cisplatin chemotherapy.

BACKGROUND: Response to cisplatin-therapy is assumed to be related to the formation of platinum (Pt)-DNA adducts. Measurement of these adducts prior to therapy could be of value to improve cisplatin based cancer therapy. MATERIALS AND METHODS: We determined Pt-GG and Pt-AG adduct levels by use of 32P-postlabeling after ex vivo cisplatin treatment of fragments of head and neck squamous cell carcinoma (HNSCC) xenografts (five lines), and of tumor biopsies from patients with HNSCC (n = 8) and testicular cancer (n = 8). RESULTS: Adduct levels in fragments (3 x 3 x 3 mm) exposed to 10 to 80 microM cisplatin for one hour, showed positive correlations with the in vivo response to cisplatin treatment (P < 0.05), as well as with the xenograft adduct levels observed after in vivo cisplatin treatment (P < 0.02). After an additional five-hour drug-free incubation period the correlations were absent. When patient tumor fragments were exposed ex vivo to 80 microM cisplatin for one hour, adduct levels were similar in HNSCC and testicular cancer. Persistence of adducts was observed for testicular cancer in the additional drug-free period. The adduct levels in the samples of two HNSCC patients who received cisplatin chemotherapy were in line with the hypothesis that higher adduct levels are associated with a better response. CONCLUSION: Our preliminary results show that analysis of DNA adducts following ex vivo drug treatment is a feasible approach towards a predictive assay, which warrants further investigation.

Adult↗
PubMed1999

Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo.

Total platinum contents and cisplatin-DNA adduct levels were determined in vivo in xenografted tumour tissues in mice and in vitro in cultured tumour cells of head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to cisplatin. In vivo, a panel of five HNSCC tumour lines growing as xenografts in nude mice was used. In vitro, the panel consisted of five HNSCC cell lines, of which four had an in vivo equivalent. Sensitivity to cisplatin varied three- to sevenfold among cell lines and tumours respectively. However, the ranking of the sensitivities of the tumour lines (in vivo), also after reinjection of the cultured tumour cells, did not coincide with that of the corresponding cell lines, which showed that cell culture systems are not representative for the in vivo situation. Both in vitro and in vivo, however, significant correlations were found between total platinum levels, measured by atomic absorption spectrophotometry (AAS), and tumour response to cisplatin therapy at all time points tested. The levels of the two major cisplatin-DNA adduct types were determined by a recently developed and improved 32P post-labelling assay at various time points after cisplatin treatment. Evidence is presented that the platinum-AG adduct, in which platinum is bound to guanine and an adjacent adenine, may be the cytotoxic lesion because a significant correlation was found between the platinum-AG levels and the sensitivities in our panel of HNSCC, in vitro as well as in vivo. This correlation with the platinum-AG levels was established at 1 h (in vitro) and 3 h (in vivo) after the start of the cisplatin treatment, which emphasizes the importance of early sampling.

Animals↗
PubMed1998

Gene-mutation assays in lambda lacZ transgenic mice: comparison of lacZ with endogenous genes in splenocytes and small intestinal epithelium.

Comparison of results derived from transgenic animal gene-mutation assays with those from mutation analyses in endogenous genes is an important step in the validation of the former. We have used lambda lacZ transgenic mice to study alkylation-induced mutagenesis in vivo in (a) lacZ and hprt in spleen cells, and (b) lacZ and Dlb-I in small intestine from lambda lacZ+/0/Dlb-Ia/b mice. Induction of mutations by ethyl- and methylnitrosourea (ENU, MNU) and ethyl methanesulphonate (EMS) was investigated at 7 weeks after a single i.p. dose of each of these chemicals. In the small intestine, treatment with various dosages of ENU (10-150 mg/kg) resulted in a linear dose-response in both lacZ and Dlb-I. MNU (30 mg/kg) was also mutagenic in lacZ and Dlb-I, while EMS (250 mg/kg) did not significantly induce mutations in either gene. In spleen, ENU gave a linear dose-related response in both lacZ and hprt, MNU induced mutation sin both lacZ and hprt, and EMS was only positive for lacZ. No differences in response were observed between single and split-dose treatment with ENU (1 x 50 or 5 x 10 mg/kg with a 1- or 7-day interval), both in spleen and small intestine, except for lacZ in small intestine, where the single high dose gave a significantly higher induction than the split dose with the 7-day interval. The overall results suggest that mutagenic effects of fractionated doses are generally additive. In most cases, the induction factor (ratio treated over controls) for mutations in lacZ was lower than that for hprt and Dlb-I, presumably due to a higher background in lacZ and/or a lower mutability of lacZ. The general concordance between the data for lacZ and the endogenous genes indicates that lambda lacZ transgenic mice are a suitable model to study induction of gene mutations in vivo.

Alkylating Agents↗
PubMed1998

Comparison of immunoaffinity chromatography enrichment and nuclease P1 procedures for 32P-postlabelling analysis of PAH-DNA adducts.

32P-postlabelling analysis for detecting DNA adducts formed by polycyclic aromatic compounds is one of the most widely used techniques for assessing genotoxicity associated with these compounds. In cases where the formation of adducts is extremely low, a crucial step in the analysis is an enrichment procedure for adducts prior to the radiolabelling step. The nuclease P1 enhancement procedure is the most established and frequently used of these methods. An immunoaffinity procedure developed for class specific recognition for polycyclic aromatic hydrocarbon (PAH)-DNA adducts has therefore been compared with the nuclease P1 method for a range of DNA adducts formed by PAHs. The evaluation was carried out with skin DNA from mice treated topically with benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, 5-methylchrysene or chrysene. The immobilised antibody had the highest affinity for adducts structurally similar to the BPDE-I-deoxyguanosine adduct ([+/-]-N2-(7r,8t,9r-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-1 0t-yl)-2'-deoxyguanosine) against which the antibody had been raised. Of the PAH-modified DNAs evaluated, the maximum adduct recovery was obtained for DNA containing the BPDE I-deoxyguanosine adduct. With DMBA-modified DNA, the profiles of adducts recovered from the column were similar when the column material was treated either with a digest of DMBA-modified DNA or with 32P-labelled DMBA adducts. I-compounds (endogenous adducts in tissue DNA of unexposed animals), which had similar chromatographic properties to PAH-DNA adducts, were not enriched by the immunoaffinity procedure. Compared to the simple nuclease P1 enhancement procedure, the immunoaffinity methods were lengthier and more labour intensive. Advantages of the immunoaffinity procedure include: specificity, allowing the selective detection of a certain class of adducts: efficient adduct enrichment, providing a viable alternative to other enrichment procedures; adequate sensitivity for model studies and the potential to purify adducts for further characterisation. However, as a general screen for detecting the formation of DNA adducts, the nuclease P1 procedure was viewed as the initial method of choice since it was capable of detecting a wider range of PAH-DNA adducts.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

The formation and repair of cisplatin-DNA adducts in wild-type and cisplatin-resistant L1210 cells: comparison of immunocytochemical determination with detection in isolated DNA.

We have studied the formation and repair of cisplatin-DNA adducts in wild-type mouse leukemia L1210/0 cells and in the sublines L1210/2 and L1210/5, which differ in cisplatin sensitivity. In a colony-formation assay these sublines were 9- and 22-fold more resistant compared to L1210/0, respectively. Cisplatin-induced DNA modification was studied at the cellular level by immunocytochemistry with antiserum NKI-A59 raised against cisplatin-treated DNA. Levels of nuclear staining immediately after a 1-h treatment were similar to those seen after a 24-h post-incubation in drug-free medium. Clear differences in DNA platination were found between the cell lines: immediately after exposure, L1210/2 and L1210/5 showed only 32 and 14%, respectively, of the nuclear staining observed in L1210/0, and 48 and 13% after 24 h. In these experiments, adduct-specific nuclear staining was quantified as the area under the adduct versus concentration curves (AUC). The formation and repair in these cell lines of the bifunctional adducts cis-Pt(NH3)2d(pGpG) (Pt-GG), cis-Pt(NH3)2d(pApG) (Pt-AG) and cis-Pt(NH3)2(dGMP)2 (G-Pt-G) were studied with an enzyme-linked immunosorbent assay (ELISA). No relation between repair and resistance was observed. The results suggest that differences in induced DNA platination levels, rather than in repair, are responsible--at least in part--for the differences in cisplatin resistance. A mechanism such as an increased tolerance of the resistant cells to plantinum-DNA damage may also be involved.

Animals↗
PubMed1998

Influence of nucleotide excision repair on N-hydroxy-2-acetylaminofluorene-induced mutagenesis studied in lambda lacZ-transgenic mice.

To study the influence of nucleotide excision repair (NER) on mutagenesis in vivo, ERCC1 +/-, XPA-/-, and wild-type (ERCC1+/+ and XPA+/+, respectively) lambda lacZ-transgenic mice were treated i.p. with N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and lacZ mutant frequencies were determined in liver. No significant effect of the treatment on the mutant frequency in wild-type or ERCC1-heterozygous mice was observed. The liver mutant frequency appeared to be significantly increased in treated XPA-/- mice only. To distinguish N-OH-AAF-induced from spontaneous mutations, lacZ mutants derived from treated XPA-/- mice were subjected to DNA-sequence analysis and the spectrum obtained was compared to that established for lacZ mutants in liver of PBS-treated lambda lacZ-transgenic mice of the parent strain 40.6. The N-OH-AAF-induced mutation spectrum appeared to be significantly different from the spontaneous mutation spectrum: the former consisted of mainly (19/22) single bp substitutions targeted at G, of which the majority (12/19) were G:C-->T:A transversions, suggesting that N-(deoxyguanosin-8-yl)-2-aminofluorene [dG-C8-AF], the major DNA adduct in N-OH-AAF-treated mice, is the premutagenic lesion. After analysis of 21 spontaneous mutants, only ten single bp substitutions targeted at G were found, of which five were G:C-->T:A transversions. This study with XPA-/- lambda lacZ-transgenic mice shows that one of the components of NER, that is, the XPA protein, suppresses mutagenesis in vivo.

Animals↗
PubMed1998

Monitoring of occupational exposure to polycyclic aromatic hydrocarbons in a carbon-electrode manufacturing plant.

An investigation is presented of occupational exposure to polycyclic aromatic hydrocarbons (PAH) in a carbon-electrode manufacturing plant, as assessed by three monitoring methods, viz. environmental monitoring of the external dose by analysis of personal air samples, biological monitoring of the internal dose by analysis of urinary 1-hydroxypyrene (1-OHpyrene), and biological effect monitoring by dosimetry of PAH-DNA adducts in blood lymphocytes. On the basis of job conditions, workers at the plant were divided into three groups with presumed low, intermediate and high exposure to air-borne PAH, respectively. All air samples showed levels of total PAH below the current MAC-value in the Netherlands, which is 200 micrograms/m3, whereas the benzo[a]pyrene level was occasionally higher than the recommended concentration of 2 micrograms/m3. The values of 1-OHpyrene in urine from the intermediate and high exposure groups were significantly higher than those of the low exposure group, namely 3.6- and 8.2-fold, respectively. Clear external and internal exposure was thus demonstrated for workers of the high and intermediate exposure groups, but this did not result in a measurable effect at the DNA level in blood lymphocytes. Tobacco smoking, on the other hand, caused a significant increase of the levels of PAH-DNA adducts but did not affect 1-OHpyrene values. These data suggest that smoking is a more important risk factor for adverse health effects, i.e. cancer, than occupational exposure to PAH in this plant.

Air Pollutants, Occupational↗
PubMed1998

Role of glutathione, glutathione S-transferases and multidrug resistance-related proteins in cisplatin sensitivity of head and neck cancer cell lines.

Resistance to chemotherapy is a major problem in the treatment of patients with head and neck squamous cell carcinoma (HNSCC). Important factors involved are drug detoxification by glutathione (GSH) and reduced drug accumulation due to active transport out of the cell by so-called 'multidrug resistance-related proteins'. We have studied a panel of eight HNSCC cell lines showing differences in sensitivity to the anti-cancer drug cisplatin. Our previous studies indicated that the IC50 values were inversely correlated with the intracellular accumulation of platinum (Pt). In the present study, cellular GSH levels were found not to be related to the IC50 values. The expression levels of the enzymes glutathione S-transferase (GST) alpha, mu, and pi, the multidrug resistance-related proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP) were determined semiquantitatively by means of immunocytochemistry. The levels of the GSTs, P-gp and LRP were not found to be correlated with the IC50 values of the HNSCC cell lines. Surprisingly, however, an inverse correlation was found between MRP levels and IC50 values. The MRP expression levels were in agreement with the results of the MRP functional assay, based on the transport of calcein across the cell membrane as performed for two of the cell lines. Further studies should prove whether other pump mechanisms or DNA repair are involved in the cisplatin accumulation and the subsequent HNSCC cell growth inhibition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Biological effect markers for exposure to carcinogenic compound and their relevance for risk assessment.

In this review data are summarized on biomarkers that are used for biological effect monitoring of human populations exposed to genotoxic carcinogens. The biomarkers are DNA and protein adducts and cytogenetic effects. Most of these biomarkers are relevant for the process of carcinogenesis. Emphasis is on providing information on the properties of the biomarkers and on their relevance for predicting cancer risk. Overviews are presented of: (1) studies on effects of exposure in target tissues of human origin obtained by surgical biopsies or autopsies, (2) epidemiological studies on healthy (cancer-free) individuals, correlating the putative occupational, lifestyle or environmental exposure with increased levels of biomarkers in blood cells, and (3) studies with animal models on the relation between biomarkers and cancer. Finally, on the basis of epidemiological data the possibilities were explored to use biomarker data to estimate the risk of death due to cancer. For several biomarkers the increment of the cancer mortality risk was calculated on the basis of a lifetime doubling of the biomarker level.

Animals↗
PubMed1998

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine.

Groups of lambda lacZ transgenic mice were treated i.p. with N-nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed for up to 14 days in various tissues. Adduct induction in the liver exceeded by at least one order of magnitude than observed in the next nearest target tissue (lung), and was approximately linearly related to dose, except for O6-methylguanine after the first dose of 1 mg/kg which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days. Small but marginally significant increases in mutant frequency were consistently observed in the spleen after all three modes of treatment. A lack of proportionality between mutation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-related cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant frequency), NDMA was found to increase the frequency of GC-->AT mutations (with a concomitant shift of their preferential location from CpG sites to GpG sites), which made up approximately 60% of the induced mutations. Surprisingly, NDMA also caused a significant increase in deletions of a few (up to 11) base-pairs (22%).

Animals↗
PubMed1998

DNA adducts, mutant frequencies, and mutation spectra in various organs of lambda lacZ mice exposed to ethylating agents.

To investigate tissue-specific relations between DNA adducts and mutagenesis in vivo, lambda lacZ transgenic mice were treated i.p. with N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). In liver, bone marrow, and brain DNA from mice sacrificed at several time points after treatment O6-ethylguanine (O6-EtG) and N7-ethylguanine (N7-EtG) levels were determined as well as the mutant frequency (MF) in lacZ. In liver DNA of ENU- and DEN-treated mice, the bulk of O6-EtG was removed at 3 days after treatment, while the MF continued to increase thereafter. This suggests that O6-EtG is not the major premutagenic lesion in the liver. Indeed, sequence analysis of mutants showed only 24% GC-->AT transitions, consistent with the O6-EtG lesion, and 28% TA-->AT transversions, expected from O2-ethylthymine. In bone marrow after ENU treatment, a maximum mutation induction occurred at 3 days post-treatment, of which 43% were GC-->AT mutations and 22% were TA-->AT mutations. This suggests that in bone marrow O6-EtG may be a major premutagenic lesion at the 3-day time point. In liver and bone marrow, EMS treatment gave rise to a high level of N7-EtG and a low level of O6-EtG but no increase in MF. No adducts or mutation induction were observed in bone marrow of DEN-treated mice. No MF increase was observed in the brain of either ENU- or EMS-treated mice, although O6- and N7-adducts were present.

Animals↗
PubMed1997

The use of benzo[a]pyrene diolepoxide-modified DNA standards for adduct quantification in 32P-postlabelling to assess exposure to polycyclic aromatic hydrocarbons: application in a biomonitoring study.

The 32P-postlabelling assay is one of the most sensitive methods for detection of DNA adducts induced by exposure to genotoxic chemicals. Under optimal conditions, detection limits of one adduct per 10(9)-10(10) nucleotides have been reported. This sensitivity now allows monitoring of occupational and even environmental exposure of humans to certain classes of chemicals, mainly polycyclic aromatic hydrocarbons (PAH). Despite its widespread use, 3P-postlabelling is still not a standardized method. Rigorous interlaboratory comparisons are scarce, and those that have been undertaken often show rather different results, both in relative and in absolute values, for the amounts of DNA adducts in the same samples. Furthermore, the optimization of many steps in the procedure has still not been given adequate attention. This paper deals with some technical aspects of detection of PAH-DNA adducts by 32P-postlabelling, in particular with assay calibration and adduct quantification. For this purpose, benzo[a]pyrene (BP)-modified DNA standards were prepared, the adduct contents of which were determined by use of an independent fluorometric method, viz. synchronous fluorescence spectrophotometry (SFS). These BP-DNA standards are processed along with the test samples throughout the entire 32P-postlabelling procedure, from the enzymic digestion up to and including the determination of radioactivity in adduct spots on the chromatogram. As such, these reference samples can be considered as external standards for inter-assay calibration. This method for adduct quantification was compared with the commonly used relative adduct labelling (RAL) and comparative dAMP labelling, which appeared to give rise to an underestimation of adduct levels. The method was applied in a biomonitoring study among workers in a carbon-electrode manufacturing plant, exposed to PAH. Although DNA adduct levels in peripheral blood lymphocytes of exposed workers, as determined by 32P-postlabelling, were not significantly different from those of controls, a significant difference was seen when smokers and non-smokers were compared.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1997

Relationship between the parameters cellular differentiation, doubling time and platinum accumulation and cisplatin sensitivity in a panel of head and neck cancer cell lines.

Patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin show a large inter-individual variation in tumor response. Little is known about factors that contribute to this variation. The aim of our study was to correlate the sensitivity to cisplatin with a number of cellular parameters using a panel of 10 human HNSCC cell lines. A 7-fold variation in response after 72 hr of exposure to cisplatin as determined in a colorimetric proliferation assay was observed. The IC50 values did not correlate with the DNA index, the cellular doubling time or the expression of differentiation markers. Intracellular platinum (Pt) concentrations were measured by atomic absorption spectroscopy after exposing the cells to 10 microM cisplatin for 1-72 hr. The intracellular Pt levels increased up to 24 hr. One cell line, derived from the tumor of a patient previously treated with radiotherapy, accumulated much more Pt than the other cell lines. For these other cell lines, a significant positive correlation was found between Pt accumulation and sensitivity. In conclusion, cisplatin-induced growth inhibition in HNSCC in vitro is generally positively correlated with cellular Pt levels. However, the fact that occasionally cancer cells can survive despite high intracellular Pt levels indicates that additional parameters are needed to explain a response unequivocally.

Adult↗